sign in sign up
<<
Home , Alverine, Antispasmodic, Cimetropium bromide, Fenoverine, Mebeverine, Otilonium bromide

DOI: https://doi.org/10.22516/25007440.309 Review articles The role of in managing

Valeria Atenea Costa Barney,1* Alan Felipe Ovalle Hernández.1

1 Internal Medicine and Gastroenterology specialist Abstract in San Ignacio University Hospital, Pontificia Universidad Javeriana, Bogotá, Colombia. Although antispasmodics are the cornerstone of treating irritable bowel syndrome, there are a number of an- tispasmodic currently available in Colombia. Since they are frequently used to treat this disease, *Correspondence: [email protected] we consider an evaluation of them to be important.

...... Received: 26/10/18 Keywords Accepted: 11/02/19 , irritable bowel syndrome, , , Mebeverin, .

INTRODUCTION consistency. The criteria must be met for three consecutive months prior to diagnosis and symptoms must have started Irritable bowel syndrome (IBS) is one of the most fre- a minimum of six months before diagnosis. (3, 4) quent chronic gastrointestinal functional disorders. It is There are no known structural or anatomical explanations characterized by recurrent associated with of the pathophysiology of IBS and its exact cause remains changes in the rhythm of bowel movements with either or unknown. Nevertheless, several mechanisms have been both and . Swelling and are proposed. Altered gastrointestinal motility may contribute frequent occurrences. (1) to changes in bowel habits reported by some patients, and a IBS is divided into two subtypes: predominance of cons- combination of spasms, visceral hypersen- tipation (20-30% of patients) and predominance of dia- sitivity and abnormalities of central pain processing may rrhea (20-30% of patients). When both constipation and explain abdominal pain, which is an essential part of the diarrhea are combined, it is called mixed IBS (up to 45% of complex of symptoms. (5) patients) and IBS of undetermined type when the pattern of It is estimated that IBS affects 11% of the world’s popu- bowel movements is intermediate and cannot be classified lation. In Europe, Asia and the United States its prevalence as diarrhea or constipation. It is noteworthy that abdominal varies from 10% to 20%. The lowest prevalence in South pain occurring more than once a week plus the temporal Asia (7%) while the highest is in South America (21%). relationship of pain with defecation are what theoretically In Western countries it is twice as frequent in women. (6) differentiates IBS from functional constipation. (2, 3) IBS has a significant impact on health-related quality of According to the Rome IV criteria, IBS is diagnosed by life, results in lower labor productivity, higher absenteeism abdominal pain that recurs at least one day a week plus two and increased use of health care with its attendant costs. In or more of the following: pain is associated with defeca- 2005, direct medical costs attributed to IBS in the United tion; pain is related to a change in the frequency of bowel States were estimated at USD 1.5 to 10 billion per year. (1) movements; and/or pain is related to a change of stool IBS can also affect the doctor-patient relationship since

© 2019 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología 267 ineffective control of symptoms can decrease the credibi- also play an important role in the development of visceral lity of doctors and encourage the patient to seek additional hypersensitivity because they produce and release sero- opinions. (7) tonin which activates 5-HT3 receptors located in afferent A heterogeneous group of medications called antispas- sensory neurons. (17) modic or spasmolytic drugs has been used in IBS therapy Abnormalities in colonic motility patterns are characteri- for decades. They act as direct smooth muscle relaxants zed by hyperreactivity due to prolonged increase of colonic (, mebeverin, peppermint oil), motor activity after meals, increased motor activity in res- agents (butylscopolamine, hioscin, , ponse to stressors or cholecystokinin (CCK), and increa- pyrenzepine) or calcium channels blockers ( sed motor response to abdominal distention. (18) citrate, ethyl bromide, pinaverium bromide). Their goal is to Visceral hypersensitivity alone is not painful, but it can reduce symptoms caused by defecation through increasing cause abdominal pain in IBS patients due to the effect of colonic transit time, improving stool consistency and/or any intense stimulus such as an exaggerated contraction of reducing stool frequency. (2) The pharmacological action the colon. (19) Nevertheless, it has not been possible to of these agents is not always clear, and their mechanisms establish a clear relationship between visceral hypersen- are often mixed. However, metaanalyses of studies com- sitivity and motility disorders, and these two factors have paring antispasmodics with placebos or other treatments generally been considered to be independent, and both have consistently confirmed the positive effects of these require effective treatment. (20) drugs, and their side effect profiles have been excellent. (8) Voltage Dependent Calcium Channels PATHOPHYSIOLOGY Voltage-dependent calcium channels play a fundamental The pathogenesis of IBS is considered to be multifactorial. role in the intestine and in pharmacological management A history of gastrointestinal infections, colonic or bacterial of IBS. These ionic channels mediate calcium influx in res- flora of an altered small intestine, increased intestinal per- ponse to membrane depolarization, and they regulate intra- meability and immune activation may all play roles in the cellular processes such as contraction, secretion and neu- development of the disease. (9) Signals from the gastroin- rotransmission in a variety of cells. (21) Calcium channels testinal tract are processed in the brain and can influence are classified by their properties and pharmacology. They motility, secretion and immune function. The brain-gut include L-type calcium channels (long duration). They axis is essential for regulation of the gastrointestinal sys- are high conductance channels that produce long-lasting tem, so structural or functional alteration can lead to the depolarization and which are inhibited by dihydropyridine development of disorders such as IBS. (10) Consequently, derivatives (DHP). (22, 23) Currents associated with this psychological factors and chronic stress may also be invol- type of channel are important for muscle and endocrine ved in triggering symptoms. (11) cells in which contraction and secretion of substances are Abnormal intestinal motility and visceral hypersensitivity mediated. (21) remain the main factors in the pathogenesis of the disease. Type N (neuronal) currents are also durable, but require (12) Intraluminal factors such as serine proteases may strongly negative potentials for complete elimination of increase colonic permeability of IBS patients by activating inactivation and strong depolarization for activation. (23) the protease-activated receptor-2. This results in visceral Three other channels have been identified in Purkinje hypersensitivity. (13) Similarly, luminal cysteine ​​proteases cells. Type P currents are blocked by low concentrations of have been shown to increase colonic permeability through ω-agatoxin, while type Q only responds to high concentra- degradation of binding proteins resulting in visceral hyper- tions. Residual currents, which were resistant to all known sensitivity possibly secondary to local microinflammation. calcium blockers at the time of their discovery, were called (14) Immune activation of the colonic mucosa has been type R (resistant). Type T (transient) voltage-dependent found to be significantly greater in IBS patients than in calcium channels are characterized by small and transient healthy controls. (15) In addition, mast cells have been conductance activated by weak depolarization. (23) These implicated in the development of IBS. One study found currents are responsible for modulating the action poten- that the number of mast cells in the colonic mucosa and tial and the performance of pacemakers. the amounts of trypsin and histamine they released were In the 1980s DHP antagonists became the first calcium markedly higher in IBS patients than in controls. (16) Mast antagonists to be used medically. They block L channels cells in the vicinity of nerve endings has been significantly and are used to treat hypertension by exploiting their pro- correlated with the severity and frequency of abdominal perties as vasodilators. (22) Calcium antagonists have no pain and discomfort in IBS patients. Enterochromaffin cells effect on skeletal muscle, but they can have some influence

268 Rev Colomb Gastroenterol / 34 (3) 2019 Review articles on heart muscle through reduction of activity and con- of the days to less than one day per week while the patients duction of pacemakers. Because IBS includes abnormal who took placebos continued to have one to three episodes gastrointestinal motility, calcium antagonists used for car- per week. During the 10-week follow-up period after the diovascular disease appear to have potential for relieving end of treatment, the likelihood of recurrence of symptoms symptoms by relaxing the smooth muscles of the colon. was significantly higher in the placebo group than in the , which has spasmolytic properties, was pro- otilonium bromide group. (28, 29) This finding may be posed as a possible IBS treatment in the late 1980s. (24) explained by the prolonged persistence of ethyl bromide in However, cardiovascular side effects have seriously limited the colon wall due to its lipophilic properties. (25) the application these calcium antagonists. This led resear- Among the most commonly reported side effects asso- chers to search for other substances that act selectively ciated with the use of ethyl bromide are dry mouth, , within the . and dizziness. These may be caused by peripheral and central muscarinic antagonism and may be explained by the known ANTI-SPASMODIC DRUGS ability of otilonium to bind muscarinic receptors. (27) Otilonium bromide has been evaluated in 5 randomized These medications act by inhibiting the action of acetyl- controlled studies which included a total of 791 patients. on muscarinic receptors or by blocking calcium (29-33) A metaanalysis found evidence of a beneficial channels in the gastrointestinal smooth muscle. As a class, effect [risk ratio (RR) = 0.70, 95% confidence interval antispasmodics have been used in the treatment of IBS for (CI): 0.54-0.90; number needed to treat (NNT): 5, 44% many years. They treat the subgroup of IBS patients who CI, p = 0.13], but there was borderline heterogeneity have abnormal contractility of the gastrointestinal smooth among study results (I2 = 44%, p = 0.13). The Colombian muscle and altered gastrointestinal transit which contri- Association of Gastroenterology (Asociación Colombiana bute to pain and altered bowel habits. (25) de Gastroenterología - ACG) clinical practice guidelines strongly recommends the use of ethyl bromide for increas- Otilonium Bromide ing the frequency of overall improvement of symptoms in IBS patients but the quality of evidence is still low. Otilonium bromide’s structure consists mainly of qua- ternary ammonium, so it is weakly absorbable from the Pinaverium Bromide gastrointestinal tract. Experimental studies show that it accumulates in the walls of the gastrointestinal tract after Pinaverium bromide, a derivative of quaternary ammo- oral administration and is almost completely excreted in nium, is poorly absorbed and has pronounced pharmaco- feces. (25) Otilonium bromide not only blocks L-type and logical effects in the gastrointestinal tract rather than in car- T-type calcium channels, but also the M1, M2, M4 and M5 diovascular system. (34) Its gastrointestinal absorption rate muscarinic receptors. The antagonistic effects of otilonium is low and is characterized by hepatobiliary excretion. (35) bromide on the M3 coupled calcium signaling pathway in Its effects are very similar to those of established L-type human colonic crypt cells suggests antisecretory action in calcium channel blockers (, ) since patients who have the diarrhea type of IBS. Antagonism of it reduces the plateau phase of slow waves which inhibits neuroquinine-2 receptors (NK-2) also causes spasmolysis calcium influx and prevents subsequent contractions. (36) while reducing peripheral sensory afferent transmission to It has also been shown to inhibit the the central nervous system, possibly contributing to greater (ACh)-induced contractile response of smooth muscle in efficacy. (26, 27) These effects suggest that otilonium bro- dog and rat colons. Acetylcholine is a neurotransmitter of mide may be effective at reducing spasms and abdominal the intrinsic nerves. (36) Similarly, in smooth pain, the two main symptoms of IBS. (2) muscle cells of the colon isolated from normal or inflamed Otilonium bromide has been evaluated for management human colons, it inhibits contraction induced by other of abdominal pain in IBS patients in a clinical trial. Patients agonists (CCK). (37) The involvement of sensory afferent diagnosed according to the Rome II criteria were randomly neurons in IBS has been demonstrated, and this could also assigned to case and control groups. They received either explain the efficacy of pinaverium bromide for treating 40 mg of ethyl bromide or a placebo three times a day for motility disorders and intestinal hypersensitivity, two key 15 weeks. Patients who took otilonium bromide had less IBS symptoms. frequent pain, bloating and bowel movements than did the A pilot study of 12 IBS patients has used surface electrom- control patients who took placebos. The outstanding result yography to study how treatment with pinaverium bromide of this study was that otilonium bromide significantly redu- affects colonic motility. Surface electromyography was ced the frequency of abdominal pain from more than half used during a two hour fasting period and a postprandial

The role of antispasmodics in managing irritable bowel syndrome 269 period of two hours after a standard meal prior to and after A multicenter, randomized, double-blind, non-inferio- 10 days of treatment with 50 mg of pinaverium bromide rity clinical study of 197 patients has compared taken three times a day. Principal IBS symptoms including with trimebutine. Subjects were randomized to receive 100 abdominal pain, bloating and impaired bowel habits began mg of fenoverine three times a day or 150 mg of trimebu- to improve on day 4 of treatment. Abnormal patterns of tine three times a day for 8 weeks. The primary evaluation colonic motility including greater frequency, greater extent criterion was the proportion of patients who experienced a of contractions and impaired rhythm in motor activity 30% reduction of baseline abdominal pain by week eight as decreased after 10 days of treatment. A continuation of measured by the scale of intestinal symptoms. (44) that study included 22 IBS patients and 7 healthy controls. Assessment criteria were changes in abdominal disten- (38) Healthy controls received no treatment, but served sion, diarrhea, constipation, and general satisfaction scores. as controls for electromyographic measurements. The Fenoverine was found to be not inferior to trimebutine at study protocol was as described above, except the duration week eight (treatment difference, 1.76%; 90% CI: 10.30 to of pinaverium bromide therapy was extended to 14 days. 13.82; p = 0.81). Fifty-four of seventy-eight patients (69.23%) The results showed that fasting and postprandial colonic who took fenoverine and 56 of 83 patients (67.47%) who motility parameters in IBS patients improved in relation to took trimebutine had 30% reductions in abdominal pain or controls. These symptoms were effectively reduced in 14 discomfort compared to the baseline. (44) days of pinaverium bromide therapy. Abdominal pain and There have been two systematic reviews that compared bloating also improved significantly with treatment. trimebutine to placebos for IBS patients. Both systematic Adverse effects that have been described include hyper- reviews showed greater improvement of abdominal pain sensitivity, angioedema, constipation, drowsiness, dyspha- with trimebutine treatment than with placebos, but the gia, epigastric pain, erythema, headache, nausea, pruritus, difference was statistically significant in only one of the vertigo, vomiting and xerostomia. The use of pinaverium reviews. That systematic review was based on three rando- bromide has generally been considered safe although its mized controlled trials. It found an RR of 1.32 with a 95% use is contraindicated in pregnant women. Although there CI of 1.07 to 1.64. The difference in the other systematic are insufficient animal reproduction studies and no infor- review was not statistically significant. Its odds ratio (OR) mation on human pregnancies is available, there is a theo- was 1.28 with a 95% CI of 0.53 to 3.14. (45) retical risk of sedation and hypotonia in newborns if pina- A systematic review based on two randomized contro- verium bromide is used at the end of pregnancy. However, lled trials found that trimebutine’s overall evaluation was no cases have been reported. not significantly better statistically than was the overall eva- Evaluation of pinaverium bromide by four studies with a luation of placebos (RR: 0.97; 95% CI: 0.68 to 1.38; OR: total of 615 patients found a statistically significant improve- 1.27; 95% CI: 0.58 to 2.79). Another systematic review ment of IBS symptoms (RR = 0.56; 95% CI 0, 38-0.82) with based on a randomized controlled trial reported that there a NNT of 4 (95% CI 3-6) although the studies heterogeneity was no statistically significant difference in adverse events was statistically significant (I2 = 61%, p = 0.05). (39-42) The between trimebutine and placebos (OR: 0.62; 95% CI: ACG’s clinical practice guidelines strongly recommends 0.20 to 1.88). (45) pinaverium bromide for reducing abdominal pain in IBS Another randomized controlled trial reported that clini- patients although the quality of evidence is still low. cal recovery was observed in 94.9% of patients treated with trimebutine. Spontaneous recovery was observed in 20.5% Trimebutine of untreated patients. These findings were based on respon- ses of parents who were asked if their child had adequate Trimebutine [3,4,5-trimethoxybenzoic acid 2 (dimethy- relief of pain and discomfort related to IBS in the previous lamino)-2-phenylbutyl ester] has multifaceted modes of seven days. (45) action. Its spasmolytic activity is unique, and it has signifi- Another randomized controlled trial that compared tri- cant non-selective agonist activity for the μ, κ and δ intes- mebutine with found that there was a statistica- tinal opioid receptors. Trimebutine has been reported to lly significant improvement of abdominal pain, consistency prematurely induce phase III of the migratory motor com- and frequency of feces and flatulence compared to the refe- plex of the intestine, and it has also been shown to modu- rence values for​​ each drug after six weeks of treatment (p late visceral sensitivity. It probably acts on smooth muscles, varies between <0.01 and <0.05). However, there were no enteric nerves, and the interstitial cells of Cajal which are statistically significant differences in the improvement of key for initiation and regulation of gastrointestinal motility. symptoms between the two drugs (p values ​​range between Some studies have reported that trimebutine acts as a regu- <0.23 and <0.71). Compared to baseline, statistically signi- lator of the Ca2 + and K + channel in the intestine. (43) ficant symptom improvement was reported for both drugs

270 Rev Colomb Gastroenterol / 34 (3) 2019 Review articles after one week of treatment. Quality of life was evaluated discomfort and urgency, with improvement of Bristol stool with the IBS-QoL questionnaire. It improved statistically scale scores and frequency of bowel movements compared significantly after treatment with trimebutine or mebeve- to the baseline. (2) rine (p <0.05). In addition, patients’ improvement was sta- Nevertheless, results have been controversial in compari- tistically greater with trimebutine than with mebeverine (p sons of the effects of mebeverine with placebos and another <0.05). The authors stated that there were no differences in and results have been measured by self-control. adverse events between the two drugs, however, no quanti- A recent systematic review which included eight randomi- tative data were presented. (45) zed trials found that clinical improvement and abdominal The ACG’s clinical practice guidelines give a weak recom- pain relief with mebeverine were not statistically better mendation for trimebutine for improving abdominal pain than the results from placebos. No differences were found in IBS patients although the quality of evidence is still low. between the effectiveness of 200 mg and 135 mg doses of mebeverine. Tolerability was excellent, and there were no Mebeverine significant adverse effects. Similarly, mebeverine was not found to have better results than placebos in a study in 135 Mebeverine, a beta-phenylethylamine derived from reser- IBS patients recruited from general practice who met the pine, has relatively specific effects on smooth muscle cells Rome III criteria. Mebeverine, methylcellulose and place- without having -like effects in humans. It directly bos were compared with or without combination with cog- blocks sodium channels and inhibits the accumulation nitive behavioral therapy. (2) However, a study conducted of intracellular calcium, and in experiments with porcine in London found that cognitive behavioral therapy sessions models it was three times more potent than papaverine at plus mebeverine were beneficial and that symptom relief inhibiting the ileal peristaltic reflex. Nevertheless, other and reduction of social and labor disability persisted for up animal studies of its pharmacology have failed to demons- to 6 months after therapy. Depression and anxiety predict trate this effect. (2) poor outcomes for IBS patients treated with mebeverine, An early study by Connell found that intravenous mebe- but in cases of patients with behavioral disturbances such verine decreased all sigmoid colonic motility, especially in as avoidance the combination of mebeverine with cogni- hyperactive subjects but had less or no effect on hypoactive tive behavioral therapy may be useful. (2) subjects. Mebeverin was superior to placebos in a 12-week The clinical practice guidelines published by the ACG study of treatment in IBS patients in terms of symptom give a weak recommendation in favor of the use of mebeve- improvement and overall well-being. Mebeverin prolonged rine for treating IBS due to low quality of evidence. ambulatory manometry in 12 IBS patients and 6 healthy In conclusion, the individual effect of antispasmodics has controls, compared to placebos, and mebeverine had no sig- been difficult to interpret since there are only a small num- nificant effects on the motor complex of the small intestine. ber of studies evaluating each medication. Nevertheless, In contrast, a higher phase 2 motility index was observed in these studies have found that antispasmodics are more both diarrhea-type IBS and in constipation-type IBS. The effective treatments of IBS than are placebos. Of the medi- phase 3 motility index was also affected. These alterations cations studied, otilonium and pinaverium are quaternary in the motor activity of the small intestine by mebeverine derivatives of ammonium which are poorly absorbed in the suggest possible spasmolytic and prokinetic effects in IBS gastrointestinal tract. They act primarily at the local level by patients. (2) reducing adverse effects of this group of medications and Positive results have also been obtained in studies of reduce the risk of persistent symptoms significantly more control of symptoms in IBS that did not compare the drug than do placebos. to placebos. Significant improvement with a minimum number of adverse events was observed after 6 weeks of REFERENCES treatment with simple and sustained forms of mebeverine. A comparison of pinaverium bromide to mebeverine in 91 1. Ford AC, Moayyedi P, Chey WD, Harris LA, Lacy BE, patients with diarrhea-type IBS found that improvements Saito YA, et al. American College of Gastroenterology in overall well-being were similar in both groups: frequency Monograph on Management of Irritable Bowel Syndrome. of defecation decreased markedly, consistency of bowel Am J Gastroenterol. 2018 Jun;113(Suppl 2):1-18. doi: movements improved in both groups, and no significant 10.1038/s41395-018-0084-x. 2. Annaházi A, Róka R, Rosztóczy A, Wittmann T. Role of side effects were observed. A clinical trial that compared antispasmodics in the treatment of irritable bowel syn- the effects on diarrhea type IBS of , a 5-HT3 drome. World J Gastroenterol. 2014 May 28;20(20):6031- antagonist receptor, with those of mebeverine found that 43. doi: 10.3748/wjg.v20.i20.6031. both treatments were equally effective in reducing pain,

The role of antispasmodics in managing irritable bowel syndrome 271 3. Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ, Simren 15. Ahn JY, Lee KH, Choi CH, Kim JW, Lee HW, Kim JW, et M, et al. Bowel Disorders. Gastroenterology. 2016 May al. Colonic mucosal immune activity in irritable bowel syn- 1;150(6):1393-1407.e5. doi: 10.1053/j.gastro.2016.02.031. drome: comparison with healthy controls and patients with 4. Longstreth GF, Thompson WG, Chey WD, Houghton ulcerative colitis. Dig Dis Sci. 2014 May;59(5):1001-11. LA, Mearin F, Spiller RC. Functional bowel disorders. doi: 10.1007/s10620-013-2930-4. Gastroenterology. 2006 Apr;130(5):1480-91. doi: 16. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell 10.1053/j.gastro.2005.11.061. GS, Santini D, et al. Activated mast cells in proximity to 5. Martínez-Vázquez MA, Vázquez-Elizondo G, González- colonic nerves correlate with abdominal pain in irritable González JA, Gutiérrez-Udave R, Maldonado-Garza bowel syndrome. Gastroenterology. 2004 Mar;126(3):693- HJ, Bosques-Padilla FJ. Effect of antispasmodic agents, 702. doi: 10.1053/j.gastro.2003.11.055. alone or in combination, in the treatment of Irritable 17. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative impor- Bowel Syndrome: systematic review and meta-analysis. tance of enterochromaffin cell hyperplasia, anxiety, and Rev Gastroenterol Mex. 2012 Apr-Jun;77(2):82-90. doi: depression in postinfectious IBS. Gastroenterology. 2003 10.1016/j.rgmx.2012.04.002. Dec;125(6):1651-9. doi: 10.1053/j.gastro.2003.09.028. 6. Janssen HA, Borghouts JA, Muris JW, Metsemakers JF, 18. Lind CD. Motility disorders in the irritable bowel syndrome. Koes BW, Knottnerus JA. Health status and management of Gastroenterol Clin North Am. 1991 Jun;20(2):279-95. chronic non-specific abdominal complaints in general prac- 19. Clavé P. Treatment of IBS-D with 5-HT3 receptor antago- tice. Br J Gen Pract. 2000 May;50(454):375-9. nists vs spasmolytic agents: similar therapeutical effects from 7. Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, heterogeneous pharmacological targets. Neurogastroenterol Schiller L, Quigley EM, et al. Effect of fibre, antispasmo- Motil. 2011 Dec;23(12):1051-5. doi: 10.1111/j.1365- dics, and peppermint oil in the treatment of irritable bowel 2982.2011.01808.x. syndrome: systematic review and meta-analysis. BMJ. 2008 20. Kanazawa M, Palsson OS, Thiwan SI, Turner MJ, van Nov 13;337:a2313. doi: 10.1136/bmj.a2313. Tilburg MA, Gangarosa LM, et al. Contributions of pain 8. Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of sensitivity and colonic motility to IBS symptom seve- smooth muscle relaxants in the treatment of irritable bowel rity and predominant bowel habits. Am J Gastroenterol. syndrome. Aliment Pharmacol Ther. 2001 Mar;15(3):355- 2008 Oct;103(10):2550-61. doi: 10.1111/j.1572- 61. doi: 10.1046/j.1365-2036.2001.00937.x. 0241.2008.02066.x. 9. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal 21. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig symptoms six months after bacterial gastroenteritis and risk J. International Union of Pharmacology. XLVIII. factors for development of the irritable bowel syndrome: Nomenclature and structure-function relationships of postal survey of patients. BMJ. 1997 Mar 15;314(7083):779- voltage-gated calcium channels. Pharmacol Rev. 2005 82. doi: 10.1136/bmj.314.7083.779. Dec;57(4):411-25. doi: 10.1124/pr.57.4.5. 10. Fichna J, Storr MA. Brain-Gut Interactions in IBS. 22. Kochegarov AA. Pharmacological modulators of voltage- Front Pharmacol. 2012 Jul 5;3:127. doi: 10.3389/ gated calcium channels and their therapeutical application. fphar.2012.00127. Cell Calcium. 2003 Mar;33(3):145-62. doi: 10.1016/ 11. Levy RL, Olden KW, Naliboff BD, Bradley LA, Francisconi C, S0143-4160(02)00239-7. Drossman DA, Creed F. Psychosocial aspects of the functio- 23. Nowycky MC, Fox AP, Tsien RW. Three types of neuro- nal gastrointestinal disorders. Gastroenterology. 2006 nal calcium channel with different calcium agonist sen- Apr;130(5):1447-58. doi: 10.1053/j.gastro.2005.11.057. sitivity. Nature. 1985 Aug 1-7;316(6027):440-3. doi: 12. Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, 10.1038/316440a0. Laganière M, et al. Rectal distention testing in patients with 24. Prior A, Harris SR, Whorwell PJ. Reduction of colonic irritable bowel syndrome: sensitivity, specificity, and pre- motility by intravenous nicardipine in irritable bowel syn- dictive values of pain sensory thresholds. Gastroenterology. drome. Gut. 1987 Dec;28(12):1609-12. doi: 10.1136/ 2002 Jun;122(7):1771-7. doi: 10.1053/gast.2002.33601. gut.28.12.1609. 13. Gecse K, Róka R, Ferrier L, Leveque M, Eutamene H, 25. Camilleri M, Boeckxstaens G. Dietary and pharmaco- Cartier C, et al. Increased faecal serine protease acti- logical treatment of abdominal pain in IBS. Gut. 2017 vity in diarrhoeic IBS patients: a colonic lumenal factor May;66(5):966-974. doi: 10.1136/gutjnl-2016-313425. impairing colonic permeability and sensitivity. Gut. 2008 26. Evangelista S, Cochet P, Bromet N, Criscuoli M, Maggi CA. May;57(5):591-9. doi: 10.1136/gut.2007.140210. A distribution study with (14)C-otilonium bromide in the 14. Annaházi A, Ferrier L, Bézirard V, Lévêque M, Eutamène H, rat: evidence for selective tropism for large intestine after oral Ait-Belgnaoui A, et al. Luminal cysteine-proteases degrade administration. Drug Metab Dispos. 2000 Jun;28(6):643-7. colonic tight junction structure and are responsible for 27. Evangelista S, Giachetti A, Chapelain B, Neliat G, Maggi CA. abdominal pain in constipation-predominant IBS. Am J Receptor binding profile of Otilonium bromide. Pharmacol Gastroenterol. 2013 Aug;108(8):1322-31. doi: 10.1038/ Res. 1998 Aug;38(2):111-7. doi: 10.1006/phrs.1998.0340. ajg.2013.152.

272 Rev Colomb Gastroenterol / 34 (3) 2019 Review articles 28. Boeckxstaens G, Corazziari ES, Mearin F, Tack J. IBS and is inhibited by the calcium pinaverium bro- the role of otilonium bromide. Int J Colorectal Dis. 2013 mide. Cell Calcium. 2001 Jun;29(6):429-38. doi: 10.1054/ Mar;28(3):295-304. doi: 10.1007/s00384-012-1598-0. ceca.2001.0205. 29. Clavé P, Acalovschi M, Triantafillidis JK, Uspensky YP, 38. Wittmann T, Fehér A, Rosztóczy A, Jánosi J. [Effectiveness Kalayci C, Shee V, et al. Randomised clinical trial: otilonium of pinaverium bromide therapy on colonic motility disor- bromide improves frequency of abdominal pain, severity of ders in irritable bowel syndrome]. Orv Hetil. 1999 Feb distention and time to relapse in patients with irritable bowel 28;140(9):469-73. syndrome. Aliment Pharmacol Ther. 2011 Aug;34(4):432- 39. Zheng L, Lai Y, Lu W, Li B, Fan H, Yan Z, et al. Pinaverium 42. doi: 10.1111/j.1365-2036.2011.04730.x. Reduces Symptoms of Irritable Bowel Syndrome in 30. D’Arienzo A. D’Agostino L. L’ottilonio bromuro nel tratta- a Multicenter, Randomized, Controlled Trial. Clin mento della sindrome del colon irritabile. Rass Int Clin Ter. Gastroenterol Hepatol. 2015 Jul;13(7):1285-1292.e1. doi: 1980;60:649-56. 10.1016/j.cgh.2015.01.015. 31. Glende M, Morselli-Labate AM, Battaglia G, Evangelista S. 40. Delmont J. Interet de l’adjonction d’un antispasmodique Extended analysis of a double-blind, placebo-controlled, musculotrope au traitement des constipations douloureuses 15-week study with otilonium bromide in irritable bowel syn- des colopathies fonctionnelles par le son. Med Chir Dig. drome. Eur J Gastroenterol Hepatol. 2002 Dec;14(12):1331- 1981;10:365-70. 8. doi: 10.1097/00042737-200212000-00008. 41. Levy C, Charbonnier A, Cachin M. [Pinaverium bromide 32. Baldi F, Corinaldesi R, Ferrarini F, et al. Clinical and functio- and functional colonic disease (double-blind study]. Sem nal evaluation of octilonium bromide in the treatment of Hop Ther. 1977 Sep-Oct;53(7-8):372-4. irritable bowel syndrome: a double-blind controlled trial. 42. Virat J, Hueber D. Colopathy pain and dicetel. Prat Med. Clin Trials J. 1983;20:77-88. 1987;43:32-34. doi: 10.1097/00007890-198701000- 33. Castiglione F, Daniele B, Mazzacca G. Therapeutic strategy 00008. for the irritable bowel syndrome. Ital J Gastroenterol. 1991 43. Hussain Z, Jung DH, Lee YJ, Park H. The Effect of Nov;23(8 Suppl 1):53-5. Trimebutine on the Overlap Syndrome Model of Guinea 34. Christen MM-O, Tassignon J-P. Pinaverium bromide: A Pigs. J Neurogastroenterol Motil. 2018 Oct 1;24(4):669- acting selectively on the gastroin- 675. doi: 10.5056/jnm18049. testinal tract. Drug Dev Res. 1989 Jan 1;18(2):101-12. doi: 44. Kang SH, Jeen YT, Koo JS, Koo YS, Kim KO, Kim YS, et 10.1002/ddr.430180202. al. [Efficacy of fenoverine and trimebutine in the manage- 35. Evangelista S. Quaternary ammonium derivatives as spas- ment of irritable bowel syndrome: multicenter randomi- molytics for irritable bowel syndrome. Curr Pharm Des. zed double-blind non-inferiority clinical study]. Korean 2004;10(28):3561-8. doi: 10.2174/1381612043382972. J Gastroenterol. 2013 Nov;62(5):278-87. doi: 10.4166/ 36. Malysz J, Farraway LA, Christen MO, Huizinga JD. kjg.2013.62.5.278. Pinaverium acts as L-type calcium channel blocker on 45. Trimebutine Maleate and Pinaverium Bromide for Irritable smooth muscle of colon. Can J Physiol Pharmacol. 1997 Bowel Syndrome: A Review of the Clinical Effectiveness, Aug;75(8):969-75. doi: 10.1139/cjpp-75-8-969. Safety and Guidelines [Internet]. Ottawa (ON): Canadian 37. Boyer JC, Magous R, Christen MO, Balmes JL, Bali JP. Agency for Drugs and Technologies in Health; 2015 Nov 30. Contraction of human colonic circular smooth muscle cells

The role of antispasmodics in managing irritable bowel syndrome 273